5-Fluorouracil/Cytarabine Mutual Prodrugs
J . Org. Chem., Vol. 62, No. 26, 1997 9087
135.72, 171.56, 171.83. Anal. Calcd for C18H18O4S (330.33):
C, 65.44; H, 5.49; S, 9.71. Found: C, 65.35; H, 5.51; S, 9.79.
Hexa n ed ioic a cid ben zyl ester (p h en ylsu lfa n yl)m eth yl
173.19, 173.54. Anal. Calcd for C18H19FN2O6 (378.36): C,
57.12; H, 5.06; F, 5.02; N, 7.41. Found: C, 57.19; H, 5.07; N,
7.35.
P r ep a r a tion of Com p ou n d s 6. Gen er a l P r oced u r e.
Into a 100 mL round bottom flask was added 5 (3 mmol) and
17 mL of acetic acid. Complete dissolution occurred after
about 30 min of stirring at rt. To the solution were added 10%
Pd/C (1.0 g) and 1,4-cyclohexadiene (15.8 mmol, 1.5 mL).
Periodic monitoring by TLC indicated that the reaction was
complete after 1 h. THF (25 mL) was added to the reaction
mixture (to make it less viscous and easier to filter). The
mixture was filtered first through a cotton plug and then
through a 0.45 µm nylon membrane filter to remove the Pd/C.
The THF was removed in vacuo, and then 50 mL of heptanes
was added. The acetic acid was removed by bulb-to-bulb
distillation as an acetic acid/heptanes azeotrope. The white
solid which remained after distillation was 6. 6 often con-
ester (3b): 94% yield; IR (neat) 3465, 3065, 3038, 2931, 1735
cm-1 1H NMR (CDCl3) δ 1.66 (m, 4H), 2.35 (t, J ) 6.6 Hz,
;
4H), 5.09 (s, 2H), 5.39 (s, 2H), 7.33 (m, 10H); 13C NMR (CDCl3)
δ 24.32, 24.36, 33.96, 34.04, 66.34, 68.09, 127.49, 128.34,
128.69, 129.24, 130.49, 134.80, 136.10, 172.66, 173.14. Anal.
Calcd for C20H22O4S (358.46): C, 67.02; H, 6.19; S, 8.93.
Found: C, 66.89; H, 6.26; S, 8.80.
P r ep a r a tion of Com p ou n d s 4. Gen er a l P r oced u r e.
Diester 3 (20 mmol) was dissolved in 40 mL of CH2Cl2 in a
three-neck round bottom flask equipped with an addition
funnel and purged with argon. Sulfuryl chloride (24 mmol,
24 mL of a 1.0 M CH2Cl2 solution) was added to the addition
funnel and slowly dropped into the reaction vessel. The
mixture changed color, from clear to dark orange, upon
addition of the sulfuryl chloride. After 1 h of stirring at room
temperature, crystalline cis-4-cyclohexene-1,2-dicarboxylic acid
(20 mmol) was added to the reaction mixture via powder
funnel. The color changed again, after about 30 min of
stirring, from dark orange back to the original clear. The
mixture was stirred another 30 min, and a white precipitate
formed. The precipitate was filtered and the solvent reduced
in vacuo to produce an oily residue. The residue was dissolved
in 50 mL of diethyl ether, and the ether solution was washed
with 10% NaHCO3 (1 × 50 mL) and H2O (2 × 50 mL), dried
over MgSO4, filtered, and reduced in vacuo to afford 4 as a
clear oil.
1
tained residual acetic acid by H NMR.
Su ccin ic a cid Mon o[(5-flu or o-2,4-d ioxo-3,4-d ih yd r o-
2H-p yr im id in -1-yl)m eth yl] ester (6a ): 99% yield; mp 153-
156 °C; IR (KBr) 3432, 3045, 2936, 2852, 1745, 1695, 1661 cm-1
1H NMR (CD3OD) δ 2.62 (s, 4H), 5.66 (s, 2H), 7.89 (d, J ) 6
Hz, 1H), (DMSO-d6) δ 2.32-2.61 (m, combined with solvent
signal, > 4H), 5.51 (s, 2H), 8.02 (d, J ) 6 Hz, 1 H), 11.99 (br,
1H); 13C NMR (DMSO-d6) δ 28.79, 28.66, 70.45, 129.50 (d, J CCF
) 34 Hz), 139.42 (d, J CF ) 229 Hz), 149.26, 157.45 (J CCF ) 25
Hz), 172.09, 173.33. Anal. Calcd for C9H9FN2O6 (260.18): C,
41.55; H, 3.49; F, 7.30; N, 10.77. Found: C, 41.35; H, 3.80; N,
10.07.
Hexa n ed ioic a cid m on o[(5-flu or o-2,4-d ioxo-3,4-d ih y-
d r o-2H-p yr im id in -1-yl)m eth yl] ester (6b): 60% yield; mp
171-173 °C; IR (KBr) 3430, 3138, 3038, 2951, 2838, 1751,
Su ccin ic a cid ben zyl ester ch lor om eth yl ester (4a ):
90% yield; IR (neat) 1765, 1735 cm-1; 1H NMR (CDCl3) δ 2.70
(s, 4H), 5.13 (s, 2H), 5.66 (s, 2H), 7.33 (s, 5H); 13C NMR (CDCl3)
δ 28.77, 28.97, 66.73, 68.77, 128.27, 128.34, 128.57, 135.62,
170.44, 171.64. Anal. Calcd for C12H13O4Cl (256.69): C, 55.24;
H, 5.15; Cl, 13.66. Found: C, 55.01; H, 5.12; Cl, 13.51.
1
1735, 1700, 1660 cm-1; H NMR (DMSO-d6) ( 1.49 (t, J ) 3.6
Hz, 4H), 2.18 (t, J ) 6.4 Hz, 2H), 2.34 (t, J ) 6.4 Hz, 2H), 5.55
(s, 2H), 8.11 (d, J ) 6.6 Hz, 1H), 11.00 (br, 1H); 13C NMR
(DMSO-d6) δ 23.64, 23.78, 32.84, 33.25, 70.49, 129.43 (d, J CCF
) 34 Hz), 139.42 (d, J ) 230 Hz), 149.23, 157.40 (d, J CCF ) 26
Hz), 172.45, 174.24. Anal. Calcd for C11H13FN2O6 (288.23):
C, 45.82; H, 4.55; F, 6.59; N, 9.51. Found: C, 46.05; H, 4.66;
N, 9.51.
H exa n ed ioic a cid b en zyl est er ch lor om et h yl est er
1
(4b): 98% yield; IR (neat) 1762, 1735 cm-1; H NMR (CDCl3)
δ 1.69 (m, 4H), 2.39 (m, 4H), 5.12 (s, 2H), 5.69 (s, 2H), 7.35 (s,
5H); 13C NMR (CDCl3) δ 24.07, 24.29, 33.72, 33.93, 66.40,
68.75, 128.30, 128.38, 128.72, 136.10, 171.39, 173.10. Anal.
Calcd for C14H17ClO4 (284.74): C, 59.14; H, 6.03; Cl, 12.31.
Found: C, 59.03; H, 5.99; Cl, 12.48.
P r ep a r a tion of Com p ou n d s 7. Gen er a l P r oced u r e. In
a 100 mL round bottom flask was dissolved 6 (2mmol) in 5
mL of DMF. Pentafluorophenol (2 mmol) was added followed
by EDCI‚HCl (2 mmol). The mixture stirred at room temper-
ature for 2 h. The DMF was removed by bulb-to-bulb distil-
lation, and the resulting residue was purified (flash chroma-
tography, 40% EtOAc/CH2Cl2, solid deposition on silica gel)
to give 7. 7 must be used immediately as it decomposes on
standing.
Su ccin ic a cid 5-(flu or o-2,4-d ioxo-3,4-d ih yd r o-2H -
p yr im id in -1-yl)m eth yl ester 2,3,4,5,6-p en ta flu or op h en yl
ester (7a ): 43% yield; mp 130-131 °C; 1H NMR (CDCl3) δ 2.85
(m, 2H), 3.04 (m, 2H), 5.69 (s, 2H), 7.59 (d, J ) 5 Hz, 1H),
8.76 (br, 1H).
P r ep a r a tion of Com p ou n d s 5. Gen er a l P r oced u r e.
Into a 100 mL, three-neck flask equipped with stirring bar
and addition funnel was placed 5-fluorouracil (8.11 mmol) and
10 mL of DMF. The mixture stirred for 10 min, and then a
3-fold excess of triethylamine (24.33 mmol) was added via
syringe. The mixture stirred at room temperature for 30 min.
Freshly prepared (less than 24 h old) 4 (8.11 mmol), dissolved
in 10 mL of DMF, was added dropwise via addition funnel. A
precipitate of triethylamine hydrochloride formed after about
1 h of stirring. The stirring continued overnight (16 h), and
then the precipitate was filtered and the DMF removed by
bulb-to-bulb distillation. The resultant crude solid gave 5 as
a white solid after purification by flash chromatography (40%
EtOAc/CH2Cl2, solid deposition on silica gel with THF).
Hexa n ed ioic a cid 5-(flu or o-2,4-d ioxo-3,4-d ih yd r o-2H-
p yr im id in -1-yl)m eth yl ester 2,3,4,5,6-p en ta flu or op h en yl
ester (7b): 77% yield; mp 118 °C; 1H NMR (CDCl3) δ 1.79 (m,
4H), 2.47 (t, J ) 6.9 Hz, 2H), 2.70 (t, J ) 6.9 Hz, 2H), 5.66 (s,
2H), 7.62 (d, J ) 5 Hz, 1H), 9.39 (br, 1H).
Su ccin ic a cid ben zyl ester (5-flu or o-2,4-d ioxo-3,4-d i-
h yd r o-2H-p yr im id in -1-yl)m eth yl ester (5a ): 76% yield; mp
125-127 °C; IR (KBr) 3432, 3178, 3072, 2832, 1758, 1711, 1658
N-(1-â-D-Ar a bin ofu r a n osylcytosyl)su ccin a m ic Acid (5-
F lu or o-2,4-d ioxo-3,4-d ih yd r o-2H-p yr im id in -1-yl)m eth yl
Ester (1a ). Ara-C (0.15 g, 0.62 mmol) and activated ester 7a
(0.46 g, 1.08 mmol) were combined in 2 mL of DMF. The
mixure stirred at room temperature for 72 h. The DMF was
removed by bulb-to-bulb distillation, and a clear viscous
residue remained. The residue was dissolved in a minimum
(2-3 mL) of methanol and then rapidly precipitated out of
solution by addition of 500 mL of CHCl3 (it is critical that
contact with methanol be kept to a minimum). The precipitate
was then immediately filtered through a 0.45 µm nylon
membrane and dried in a vacumn dessicator at 60 °C. In order
to remove persistent CHCl3 after drying, the precipitate was
dissolved in 2-3 mL of deionized H2O, rapidly frozen solid,
and lyophilized. This process was repeated twice to afford 284
mg of analytically pure 1a (93%): mp 126 °C dec; IR (KBr)
3412 (br), 3078, 2931, 1721, 1654, 1565, 1491, 1391, 1314,
cm-1 1H NMR (CDCl3) δ 2.71 (s, 4H), 5.12 (s, 2H), 5.63 (s,
;
2H), 7.34 (s, 5H), 7.56 (d, J ) 5 Hz, 1H), 9.45 (br, 1H); 13C
NMR (CDCl3) δ 28.42, 28.44, 65.67, 70.55, 127.87, 128.00,
128.40, 129.47 (d, J CCF ) 34 Hz), 135.9, 139.35 (d, J CF ) 229
Hz), 149.19, 157.38 (d, J CCF ) 26 Hz), 171.66, 171.72; 19F NMR
(qualitative, no internal standard, CDCl3) δ 9.93 (d, J FH ) 5
Hz). Anal. Calcd for C16H15FN2O6 (350.30): C, 54.84; H, 4.32;
F, 5.42; N, 8.00. Found: C, 55.05; H, 4.39; N, 7.82.
Hexa n ed ioic a cid ben zyl ester (5-flu or o-2,4-d ioxo-3,4-
d ih yd r o-2H-p yr im id in -1-yl)m eth yl ester (5b): 63% yield;
mp 98 °C; IR (KBr) 3405, 3172, 3038, 2838, 1751, 1711, 1658
cm-1; 1H NMR (CDCl3) δ 1.67 (m, 4H), 2.36 (q, J ) 7 Hz, 4H),
5.11 (s, 2H), 5.63 (s, 2H), 7.35 (s, 5H), 7.62 (d, J ) 5 Hz, 1H),
9.73 (br, 1H): 13C NMR (CDCl3) δ 24.06, 24.24, 33.54, 33.85,
66.46, 69.86, 128.38, 128.40, 128.70 (d, J ) 34 Hz), 128.73,
136.07, 140.36 (d, J ) 239 Hz), 149.58, 157.22 (d, J ) 27 Hz),